Moshe Ornstein, MD, MA, Department of Hematology and Medical Oncology, Cleveland Clinic, discusses unmet needs in metastatic renal cell carcinoma (mRCC).

Although there has been much progress over the past 5 to 10 years in the treatment of patients with metastatic kidney cancer, there are remaining questions that the field must address with future research and clinical trials, Ornstein says. Much of the progress has been in treatment-naïve mRCC, but how to manage those patients after their cancer progresses on front-line therapies remains a challenge, Ornstein explains.

Many of the agents that are available for refractory RCC have response rates between 20% and 30% and poor progression-free survival, Ornstein continues. Overall, trials are aiming to discover a therapy that can produce durable benefit in patients with refractory RCC, Ornstein concludes.

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Moshe Ornstein, MD, MA, discusses unmet needs in metastatic renal cell carcinoma.


Dr. Ornstein on Unmet Needs in Refractory RCC

Moshe Ornstein, MD, MA, Department of Hematology and Medical Oncology, Cleveland Clinic, discusses the efficacy findings from a phase 2 trial (NCT03341845) examining neoadjuvant avelumab (Bavencio) and axitinib (Inlyta) in renal cell carcinoma (RCC).

The phase 2 trial examined the use of neoadjuvant avelumab and axitinib in patients with RCC who were at high risk of relapse after nephrectomy.

Of the 40 patients enrolled on the trial, 70% were male and the median age was 63, spanning a range of high-risk categories, Ornstein says. Notably, 43% of patients had node-positive disease, 20% of patients were T-4, and 28% of patients had a Fuhrman grade of 3 or 4, Ornstein explains.

The objective response rate was 30%, with all of those patients achieving a partial response, Ornstein says. Furthermore, 83% (n = 10) of the patients who had a response remained disease-free at the time of study follow-up, Ornstein explains.

Secondary end points of disease-free survival and overall survival were not met. However, at a median follow up of approximately 2 years, recurrence was seen in about one-third of patients, leaving approximately two-thirds of patients disease-free, Ornstein concludes.

Moshe Ornstein, MD, MA, discusses the efficacy findings from a phase 2 trial examining neoadjuvant avelumab and axitinib in renal cell carcinoma.


Dr. Ornstein on the Efficacy of Neoadjuvant Avelumab and Axitinib in RCC

Moshe Ornstein, MD, MA, Department of Hematology and Medical Oncology, Cleveland Clinic, discusses the benefit of neoadjuvant therapy in renal cell carcinoma.

Although adjuvant therapy is currently utilized for patients who are at high risk of recurrence, there is important rationale behind giving therapy to patients prior to surgery, Ornstein explains. Neoadjuvant therapy can decrease tumor size, enabling easier resection and allowing additional nephron sparing to preserve as much healthy kidney tissue as possible, Ornstein says.

Additionally, it is theorized that neoadjuvant immunotherapy could produce better results for patients, Ornstein continues. Data from other tumor types suggest that immunotherapy before surgery can improve disease-free survival, compared with the adjuvant setting, Ornstein concludes.

Moshe Ornstein, MD, MA, discusses the benefit of neoadjuvant therapy in renal cell carcinoma.


Dr. Ornstein on the Benefit of Neoadjuvant Therapy in RCC

Moshe Ornstein, MD, staff, Cleveland Clinic, discusses the challenges surrounding immunotherapy for patients with renal cell carcinoma.

Though checkpoint inhibitors have been impactful in this field, they do come with a handful of challenges, such as pseudoprogression, Ornstein explains. This leads to potentially having patients who seem to be progressing but are not, and are being taken off of treatment prior to them being able to have the optimal benefit.

Ornstein questions: how should physicians measure progressive disease in this setting? If a patient has progressive disease, can they be treated beyond their progression? Data from the CheckMate-025 trial showed that a handful of patients benefitted when they were treated beyond their disease progression.

Another challenge is the duration of therapy. Data suggest that there are a significant number of patients who will come off of therapy for nonprogressive disease reasons. Despite being off of therapy, they are able to sustain a long-term response without any subsequent treatment. This produces a dilemma to determine whether patients are being treated appropriately, in the sense that they are being treated continuously or indefinitely.

Dr. Ornstein on Challenges With Immunotherapy in RCC

Moshe Ornstein, MD, staff, Cleveland Clinic, discusses the role of interleukin-2 (IL-2) going forward in patients with renal cell carcinoma (RCC).

In 2017, when there are targeted therapies and immunotherapy agents, the benefit of IL-2 in metastatic RCC is that, for a subset of patients, it is one of the only therapies for which researchers have long-term data and long-term durable complete remissions (CRs).

One of the challenges with high-dose IL-2 is patient selection as it is a fairly toxic regimen with a reasonable mortality and morbidity rate, Ornstein explains. Although it is low, it still must be balanced against the durable CRs. Unfortunately, there no current predictive markers. Therefore, it is up to individual physicians to decide with their patients whether they are best suited to tolerate the toxicity of IL-2.

IL-2 is generally administered to young patients with minimal comorbidities who have clear cell RCC who don’t have metastases in the bone or in the brain, he adds.

Dr. Ornstein on Role of IL-2 in Patients With RCC

	Oncology Fellowship Is Not a Continuation of Residency

Congratulations! It took at least 4 years of college, 4 years of medical school, and 3 years of internal medicine residency to reach this point. But you’re finally here. There are no more agonizing personal statements to write, ERAS tokens to obtain, or “Why do you want to be an oncologist?” questions to answer. That’s the good news. As you begin your first year of oncology fellowship, I want to share with you a few things I’ve learned since standing in your shoes just 12 months ago.

During your first year of fellowship, you will confront challenges different from those encountered by your colleagues who have pursued specialty training in other fields such as cardiology, critical care, and gastroenterology. In most residency programs, the majority of inpatient rotations surround the traditional medical fields of general medicine, gastrointestinal medicine, intensive care, and cardiology. Inpatient oncology rotations are far less common, thus limiting your exposure to the acute medical complications faced by cancer patients. Moreover, even if you were to rotate on the inpatient oncology service, it would not be an accurate reflection of what you will experience as an oncology fellow, because the majority of oncology care takes place in the outpatient setting.

Your learning curve will be far steeper than those of your colleagues in other specialties, who gained substantial exposure to the core medical issues in their fields during their residency. Whereas words like heart failure, chronic obstructive pulmonary disease (COPD), diabetes, and hypertension roll seamlessly off the tongue of any resident, tongue twisters like blinatumomab and palbociclib do not. You’ll quickly learn that while residency may have prepared you for the acute management of a patient’s prerenal kidney injury, it did not necessarily provide you with the foundation for facing the day-to-day issues and challenges of cancer patients and their medical providers.

There’s another more subtle difference between the world of oncology and other medical fields. Think back (if you are brave enough) to your intensive care unit rotations, or time on the cardiology service. There was so much emphasis on preload, afterload, systemic vascular resistance, pressure, and flow. In other words, the emphasis was on physiology: “Why is the heart failing, why is there blood in the stool, and why are the urine casts granular?” In oncology, the focus is shifted to the pathology of disease: “What is the driver mutation of the cancer, what is the cellularity or dysplasia in the bone marrow, and what is the primary origin of the patient’s cancer?”

However, more important than the fundamental difference between pathology and physiology is the critical distinction between taking care of a patient’s medical condition and taking care of the patient. In residency, you were trained to resolve a patient’s COPD exacerbation, diurese fluid-filled lungs, and control rapid atrial fibrillation. In simple terms, your job was to identify the problem, fix it, and move on. During oncology fellowship, you will be expected to empathize with your patient’s struggle with cancer, understand how a mother’s chemotherapy schedule is interfering with her ability to care for her children, and recognize a patient’s right to choose between quantity and quality of life. The objective is not necessarily to distinguish which drug to use and when, but rather to also understand the emotional and psychological impact of the disease and its therapy.

	Research: A Few Dos and Don’ts for Your First Year

One challenge during your first year of fellowship will be to balance your excitement regarding the medical aspects of treating the disease with the equally important patient interactions, communication, and relationships. And although you are correctly thinking that this should be the case in all specialties, it is amplified in oncology, where the impact of disease is often more significant. Maintaining this balance is something that comes naturally to very few people. As you follow your attendings in clinic and in the hospital, take note of their words, phrases, and mannerisms as they discuss diagnosis, treatment, disease progression, and end-of-life issues with patients and their families. Almost anyone can follow an algorithm to determine therapy, but only the well trained can incorporate the psychosocial elements of cancer therapy into their oncologic treatment plan.

Most oncology fellowship programs have high research expectations for their fellows. That’s hopefully not news to you. Each program has a different research structure. However, as a general rule, the first year of fellowship revolves around clinical duties, while the next 2 years are more research focused. Nonetheless, there will be pressure on you to identify a mentor, begin to design a research project, and even start to think about participating in your institution’s clinical trials during your first year of fellowship. Dr Mireles-Cabodevila, director of the critical care fellowship program at the Cleveland Clinic, began his fellowship fascinated with the physiology of heart rate variability in the critically ill. For a variety of reasons, his fellowship research project failed, which prompted him to turn his experiences into the “Ten Commandments” of research during fellowship. I urge you to read these “Ten Commandments,” as they will certainly influence your approach to research during fellowship.

His advice is practical and includes common sense recommendations such as recognizing that everything takes longer than expected, that you will need more help than you think, and that you need to set deadlines. However, for those of you who won’t read the publication (even though it’s free!), I want to quote the take-home message from Commandment 8, entitled “You Can Always Say No:” 

While it may be hard to say “no,” it is generally better than saying “I could not deliver.” As a venerated mentor once said, “If you don’t use certain ‘two- letter words’ enough (ie, “no”), you’ll end up using certain ‘four-letter words’ a lot more.”

In other words, if you’ve gotten as far as an oncology fellowship, chances are you are at least moderately interested in research. As an anxious, excited, and eager- to-please first year fellow, you will meet many faculty members who would be thrilled to serve as your mentor. For example, after your leukemia rotation, you may be offered the opportunity to write a review article, or when rotating through lung cancer clinic, you may be asked to help with a retrospective data review based on your institution’s experience with a novel therapeutic. Learn to say “no.” Don’t agree to a project about which you are not excited. Remember that agreeing to a project and not seeing it to fruition is far worse than politely declining in the first place. Find the area of research that most excites you and the clinical questions that you want to answer. That is a guaranteed recipe for success.

You are entering your final stage of formal medical training. Whereas in residency you were merely one of 20, 30, or 40 residents training in internal medicine, you are now part of a select and small group of individuals. Most programs enlist only 4 to 8 hematology/ oncology fellows per year. This has critical ramifications for your current training and future career.

At this stage, your co-fellows and faculty are not merely fleeting figures in your academic and clinic training. Rather, they are potential future coworkers and employers, as well as individuals whom you may encounter time and again throughout the course of your career. Fellowship is unlike residency in that you are not constantly moving from one department to another; rather, you are developing sustained longterm relationships with faculty, advanced practitioners, and nursing staff.

In many ways, your fellowship is a 3- or 4-year interview. Your faculty are assessing whether you’re someone they would want as a future colleague and whether they would recommend you as a potential colleague to their contacts at other institutions. This is not meant to imply that you are expected to know all there is to know about oncology during your first few months of training. However, it does place a greater emphasis on the basics: be respectful to everyone, be kind, be willing to help out a colleague in need, be honest. Nurture the relationships you build during these critical years, as they will serve as the foundation for your future.

I saved the most important topic for last. As much as we yearn for more, there are still only 24 hours in a day. During the recent oncology fellowship graduation at Cleveland Clinic, Dr Matt Kalaycio, chairman of the hematology/oncology department, reminded the fellows of this fact. He explained that throughout a career in oncology, we will be asked and often required to give away our most precious asset—time&mdash;in response to demands from many sources, including patients and their families, research, and clinical duties. Especially during fellowship, as you aim to impress, it will quickly become easy for you to commit all of your time to others. He therefore asked the graduating fellows to consider the following: “I hope you will give yourselves the gift of time.”

Over the next 3 years, you will have many obligations, and it will not be difficult for you to allow your fellowship to take control of your life. Despite a plethora of data documenting the issue of burnout in oncology, there is surprisingly little mention of worklife balance during training. Whether your time away from work involves your family, exercise, religion, leisure reading, or some combination thereof, be sure you do yourself the service of ensuring an appropriate balance between your work and “life.” Physician, heal thyself—you and your patients will be grateful.

It’s been a long road and you’re nearing the end. Some of you have always dreamed of being an oncologist, and some of you have made that decision only within the last few years. Regardless of the timing of your decision, you have invested a tremendous amount of time, energy, and money in getting to where you are today. I urge you to take pride in your work. Be proud of your commitment to spend your days taking care of cancer patients. Feel fortunate to be a part of such an exciting and rapidly evolving medical field. Most importantly, remember, even in the darkest of days, to have fun. You owe yourself at least that much.

	1. Mireles-Cabodevila E, Stoller JK. Research during fellowship: ten commandments. 

Articles

As you begin your first year of oncology fellowship, I want to share with you a few things
Iâ€™ve learned since standing in your shoes just 12 months ago.

Moshe Ornstein, MD